Articular cartilage is the bearing material of diarthrodial joints. A proper understanding of the in situ response of articular cartilage under physiological loading conditions is essential in several respects. Firstly, from a basic science perspective, a knowledge of the normal mechanical function of cartilage can provide an explanation as to how cartilage can withstand the relatively harsh environment of diarthrodial joints; it is notable that, despite considerable work in the area of cartilage mechanics, the complete state of stress and strain within contacting articular cartilage layers has not been reliably determined, and consequently the physiologic loading environment of chondrocytes has not been well characterized. Secondly, proper knowledge of cartilage functional response to physiological loading can lead to a better understanding of the pathomechanical processes that might lead to cartilage degeneration and osteoarthritis through mechanical pathways. This may serve to potentially avoid or retard such degenerative processes through various clinical modalities, which properly recognize the favorable and unfavorable loading conditions of cartilage. Finally, knowledge of the loading environment of articular cartilage (such as extracellular matrix stresses and strains and interstitial fluid hydrostatic pressure) may be useful to the development of strategies to enhance tissue healing and tissue engineering of cartilage substitutes; furthermore, the functional response of such healed or engineered tissues can be correctly compared to those of normal cartilage. In this competing continuation application, we propose to build on our advances to characterize the response of articular cartilage in situ under physiological loading conditions. In a hierarchical series of progressively more complex experiments from the joint to the cellular level, our Specific Aims are to characterize (1) the change in articular thickness under normal physiological loading conditions in the human patellofemoral joint (PFJ) simultaneously with the contact stress magnitude; (2) the peak strain in the articular layer under such loading conditions, and where it occurs; (3) the peak stress in the articular layer and where it occurs; and (4) the strain environment around chondrocytes throughout the depth of the articular layer under such conditions.